CN101052426A - Injection of fibrin sealant including an anesthetic in spinal applications - Google Patents
Injection of fibrin sealant including an anesthetic in spinal applications Download PDFInfo
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- CN101052426A CN101052426A CN 200580036812 CN200580036812A CN101052426A CN 101052426 A CN101052426 A CN 101052426A CN 200580036812 CN200580036812 CN 200580036812 CN 200580036812 A CN200580036812 A CN 200580036812A CN 101052426 A CN101052426 A CN 101052426A
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Abstract
A method of treating a disc that is leaking nucleus pulposus through at least one defect in the annulus fibrosus. The method includes injecting a fibrin sealant into the disc to reduce at least a portion of the at least one defect, wherein the fibrin sealant injected into the disc comprises an anesthetic, fibrinogen and an activating compound, wherein at least a portion of the fibrin forms after injection, with the proviso that a corticosteroid is absent from the fibrin sealant injected into the disc.
Description
Author: Kevin Pauza, Brian D.Burkinshaw, Steven I.Whitlock, Mark I.Richards, Jim Rogan
[0001] this application requires the priority of the U.S. Provisional Application series number 60/623,600 of submission on October 29th, 2004, and this provisional application is incorporated this paper into as a reference.
Background of invention
[0002] generally speaking, the present invention relates to use fibrin sealant (fibrin sealant), described thus sealer for example is transported to vertebral region by injection, and described sealer comprises Fibrinogen, thrombin and anesthetis.
[0003] fibrin sealant and Fibrin Glue are well-known, and are widely used in various clinical settings.In surgical operation, when coming control over bleeding not have effect by the routine operation method that comprises stitching, ligation and burn or when unrealistic, such sealer is just pointed out is the hemostatic adminicle.In these cases, sealer is by local application.
[0004] recent, the fibrin sealant that comprises corticosteroid is used to treat disc problems, for example the crack of fibrous ring.In this respect, the U.S. 6,468,527 disclose, and compositions is injected into intervertebral disc (injection in the intervertebral disc) and treats disc problems.
Summary of the invention
[0005] putting into practice when of the present invention, fibrin sealant is injected into people's vertebral region.This sealer comprises for example thrombin of Fibrinogen and activating compounds, and they form fibrin when mixing.This sealer comprises that also anesthetis is such as local anesthetic.Having been found that this compositions provides surprising remarkable effect with respect to the fibrin sealant compositions that contains corticosteroid.Calcium ion, for example the calcium ion that is provided by calcium chloride can be included within this fibrin sealant.Fibrinogen and/or thrombin can be available from the freeze-dried component with solution reconstruct, and described solution comprises one or more additives, for example various biology preparations and abiology preparation.But in one embodiment, corticosteroid is not included within this fibrin sealant.
[0006] one wide in range aspect, the present invention is the method for a kind of treatment intervertebral disc of seepage vertebral pulp because at least one in the fibrous ring is damaged, this method comprises: inject fibrin sealant to this intervertebral disc, to reduce described at least one damaged segmental defect at least, the fibrin sealant that wherein is injected into intervertebral disc comprises Fibrinogen, anesthetis and activating compounds such as thrombin, and wherein the fibrin to small part forms after injection.Alternatively, Fibrinogen, activating compounds or both are with containing narcotic solution reconstruct.In one embodiment, the fibrin sealant that is injected into intervertebral disc lacks corticosteroid.This treatment can reduce because the amount of the nucleus material of the damaged and seepage in the fibrous ring.Described damaged can be crack in the tearing of fibrous ring, the fibrous ring, or the like.Advantageously, injected can also help to recover normal disc height and hydrostatic pressure, and these are crucial key elements.Should be appreciated that normal physiologic hydrostatic pressure can vary with each individual, this treatment can produce near normal hydrostatic pressure.As used herein, normal physical stress comprises the pressure of this scope.In one embodiment, before described injection or in the described injection, vertebral pulp and fibrous ring all not in vivo pyrogenicity so that the intervertebral disc hardening, such as what in U.S. 6,095,149 for example, discussed.In one embodiment, putting into practice when of the present invention, vertebral pulp is not removed by surgical operation, for example in the situation of all or part of diskectomy, perhaps by being used for the vertebral pulp plasty of prolapse of intervertebral disc.
[0007] another wide in range aspect, the present invention is the method at a kind of people of treatment back, this method comprise with fibrin sealant inject intervertebral disc with the sealing fibrous ring at least one is damaged, wherein this fibrin sealant comprises anesthetis, Fibrinogen and activating compounds such as thrombin, wherein Fibrinogen and thrombin are formed up to the fibrin of small part after injection, and wherein this fibrin sealant does not comprise corticosteroid.
[0008] another wide in range aspect, the present invention is the method at a kind of people of treatment back, this method is included in the mixture that anesthetis, Fibrinogen and thrombin are provided in the human disc, with the treatment fibrous ring at least one is damaged, and wherein said mixture does not contain corticosteroid.Described mixture can be provided in the intervertebral disc by injection or alternate manner.
[0009] the present invention also comprises test kit, and it comprises the component that is used for injected.This test kit can comprise for example freeze dried Fibrinogen of anesthetis, Fibrinogen, for example freeze dried thrombin of thrombin, optional at least a additive, and the pin that is used to inject described sealer spinal needle (spinal needle) for example, comprise for example bending spinal needle.Selectively, vertebra intubate (spinal canula) can be used.This test kit does not comprise corticosteroid.This test kit can be got rid of the device that heat energy is provided to intervertebral disc.This test kit can comprise contrast agent and other additives alternatively.This test kit can comprise monotubular, the bitubular or multi-barrel syringe or other fibrin sealant conveyer devices.Fibrin sealant can use traditional single chamber pin or be transferred by two-chamber or multi-cavity pin.If bilumen needle is used, then each component can be transferred by independent chamber.In one embodiment, can use bilumen needle or the multi-cavity pin that allows fibrinogen component and thrombin component to contact at needle point.Perhaps, can sequentially add fibrinogen component, then inject thrombin or other enzyme components again, these injections can or take place in two-chamber or multi-cavity pin at same pin, many pins.
[0010] another wide in range aspect, the present invention is the method that is used to make test kit, comprise: fibrinogen component, thrombin component, anesthetis component and spinal needle or polymeric catheter or spinal needle and polymeric catheter are provided, wherein this test kit does not comprise corticosteroid, and wherein this test kit does not comprise the device that heat energy is provided to intervertebral disc.
[0011] advantageously, method of the present invention and test kit help to suffer from the patient's of seepage intervertebral disc syndrome lasting pain relief, in described seepage intervertebral disc syndrome, for example, vertebral pulp leaks out from intervertebral disc by damaged (for example the tearing or the crack) in the fibrous ring.Astoundingly, have been found that the fibrin sealant that comprises corticosteroid with respect to injection, use the fibrin that does not contain corticosteroid that beat all excellent effect is provided.With respect to the method for describing in the U.S. 6,468,527, disclose in this literary composition and injected the fibrin sealant that contains corticosteroid, the invention provides beat all superior effect.Unexpectedly, comprise that narcotic fibrin sealant provides even more excellent effect.Especially, with respect to the fibrin sealant that contains corticosteroid or do not contain the fibrin sealant of corticosteroid, containing narcotic fibrin sealant provides more excellent not only instant but also persistent pain relief.
Description of drawings
[0012] Fig. 1 is the sectional view of vertebral body that shows the intervertebral space place in ring crack crack, and described ring crack crack can be treated according to an embodiment of the invention.
[0013] Fig. 2 is a sketch map of wearing intervertebral foramina (trans-foraminal) gap, and the sealer of improvement can be injected in the described gap according to an embodiment of the invention.
[0014] Fig. 3 and Fig. 4 have shown the fractional chart from the VAS of embodiment 3.
Detailed Description Of The Invention
[0015] fibrin sealant of the present invention comprises that anesthetis, fibrinogen component and activating compounds are such as Fibrinogen being converted into fibrinous thrombin.This sealer contains one or more other additives alternatively.Alternatively, Fibrinogen, thrombin or both usefulness contain the solution reconstruct of at least a described additive, and wherein said additive is not a corticosteroid.This fibrin sealant is injected into for example intervertebral disc, to seal the crack in the fibrous ring and to tear.Damaged MRI scanning and the diskogram of normally utilizing at present in the fibrous ring diagnosed.When being injected into lumbar intervertebral disc, this can treat intervertebral disc low back pain and radiculopathy skelalgia.
[0016] being used to implement Fibrinogen of the present invention comprises and will form fibrinous any Fibrinogen in human body.Fibrinogen often can obtain with lyophilized form, and must be reconstructed before using.If the thrombin solution reconstruct that contains additive, Fibrinogen also can be freezing or new system, from (from the patient who receives treatment) of body; the people comprises the human fibrinogen who compiles; reorganization, and cattle or other non-humans source, for example fish (for example salmon and sea trout).Fibrinogen is used with the amount that is suitable for specific treatment, patient etc.Freeze dried Fibrinogen can use solution, and the solution that normally contains aprotinin and calcium chloride comes reconstruct.As discussed in this article, Fibrinogen or thrombin or both come reconstruct with the solution that contains at least a additive.For example, freeze dried Fibrinogen can use following material to come reconstruct: for example, contain the saline of anesthetis or additive, contain the saline solution of aprotinin and anesthetis or additive, contain anesthetis, optional additive and calcium ion (Ca
+ 2) saline solution of the calcium ion that for example can provide by calcium chloride, perhaps contain the solution of the combination of anesthetis and/or additive.
[0017] typically, thrombin is to be used for Fibrinogen is converted into fibrinous enzyme.But other enzymes can use, for example the enzyme (for example batroxobin (batroxobin)) that obtains from snake venom, the perhaps enzyme that obtains from spider venom known in the art.As used herein, " activating compounds (activating compound) " is meant and causes Fibrinogen to form fibrinous chemical compound, and this term comprises thrombin, batroxobin, or the like.Thrombin is commercially available, normally its lyophilized form.Freeze dried thrombin before use must reconstruct.Thrombin also can be freezing or new system.Thrombin can be from body, from people or group's supply, cattle, fish (for example salmon) or other inhuman Fibrinogen nickase source, such as various Araneas or other poisonous species.Described thrombin or enzyme are so that change Fibrinogen into fibrinous any amount and be used, as is known to the person skilled in the art.Thrombin can use following material to come reconstruct: contain the saline of anesthetis and/or one or more additives alternatively, perhaps contain the saline solution of anesthetis and/or additive and calcium ion.
[0018] in practice of the present invention, fibrin sealant comprises that anesthetis is such as local anesthetic.The representative example of such local anesthetic includes but not limited to lidocaine hydrochloride (normally selling with 1.5% or 4% concentration), the SARAPIN anesthetis (aseptic aqueous solution of soluble salt and alkali, from Sarraceniaceae (Sarraceniaceae) (Herba nepenthis (Pitcher Plant)) and bupivacaine hydrochloride (have another name called marcain (marcaine), normally sell) with 0.5% and 0.75% concentration.The chemical name of lignocaine is α-lignocaine-2,6-dimethylbenzene acetamide, and IUPAC (IUPAC) name is 2-(lignocaine)-N-(2, the 6-xylyl) acetamide.The chemical name of bupivacaine is 1-butyl-N-(2, the 6-xylyl)-2-piperidine formamide, be sometimes referred to as 1-butyl-2 ', 6 '-lupetidine and dimethylaniline mono-hydrochloric salts, have registration number 14252-80-3.Perhaps, procaine (2-diethylaminoethyl 4-amino benzoic Acid hydrochlorate) or other local anesthetic can be used.In these local anesthetics, bupivacaine is preferred.In one embodiment, use contains about 0.1% to about 10% narcotic solution by weight.In another embodiment, use about 0.5% to about 5% solution.The amount of this solution can change in wide scope, and for example about 0.1mL is to the anesthetic solution of about 5mL.More typically, the amount of anesthetic solution is in the scope of the extremely about 2mL of about 0.5mL.Usually, when sealer was injected into or otherwise import intervertebral disc, used narcotic amount can ease the pain effectively.In one embodiment, anesthetis is water miscible.In one embodiment, anesthetis does not contain non-water-soluble granule.Narcotic combination can be used.Anesthetis can be injected together with Fibrinogen and thrombin, and perhaps, selectively, one or more in these components can separately be injected, before injected or injection afterwards.Anesthetis can be used (for example, the solution that contains local anesthetic is used to the reconstruct Fibrinogen, and the solution that contains the II Collagen Type VI is used to the reconstruct thrombin) at the solution that is used for reconstruct Fibrinogen and thrombin.Perhaps, Fibrinogen or thrombin are by reconstruct, and anesthetis is added into the Fibrinogen or the thrombin of reconstruct then.Perhaps, can be before or after injected injecting narcotic separately.
[0019] as used herein, term " additive " is meant antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent (antiangiogen); Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang, for example aggrecan (chondroitin sulfate and dermatan sulfate (deratin sulfate)), multipotency Dan Baijutang (versican), decorin (decorin) and disaccharidase catenin polysaccharide (biglycan); Angiogenesis inhibitor element (antiangiogenins); Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd is methylcellulose, carboxymethyl cellulose and hydroxyl-propyl methocel and derivant thereof for example; Antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor, the growth of the recovery of the tissue that its promotion is impaired and/or new health tissues, for example BMP7 and BMP2; I type and II Collagen Type VI; Collagen hydrolysate; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; Bone conduction chemical compound (osteoconductive compounds); Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage comprises from the body cartilage; Oxygen-containing component; Enzyme, such as, peroxidase for example, its mediation oxygen is from the release of this type of component; Melatonin; Vitamin; And nutrient, such as, for example glucose or other sugar.But, can predict, any additives in these additives can be individually or is jointly joined fibrin sealant.One or more additives in these additives can be injected together with described Fibrinogen and thrombin, perhaps, alternatively, one or more components in these components can be injected individually, the injection described fibrin sealant before or afterwards.The combination of these additives can be used, and be used for (for example to use different additives in the solution of reconstruct Fibrinogen and thrombin, the solution that contains first additive is used to the reconstruct Fibrinogen, and the solution that contains the II Collagen Type VI is used to the reconstruct thrombin).In addition, one or more other additives be introduced in thrombin or the fibrinogenic reconstituted solutions.Similarly, one or more in these additives can be injected with Fibrinogen and activating compounds, and perhaps, selectively, one or more in these additives can be injected separately before or after injected.In one embodiment, described additive is water miscible.In one embodiment, described additive does not contain water-insoluble particles.
[0020] for the solution that contains non-complete water-soluble additives, anticaking agent, such as, for example polysorbate can be added into to promote the suspension of this component.Ethylene glycol may should not be used as anticaking agent in the present invention.
[0021] should be appreciated that in a single day Fibrinogen contacts with thrombin, for example in the Y of dual barrel syringe type adapter, contacts that fibrin just begins to form immediately.Therefore, " injection " of term fibrin sealant, as used herein, contained any injection that in intervertebral disc, forms fibrinous component, comprise such situation, that is, some of components are owing to contacting with intervertebral disc or the actual mixing that imports before the intervertebral disc reacts, thereby form fibrin.Be equally within the scope of the present invention be, the component of fibrin sealant is sequentially injected intervertebral disc, for example inject and inject fibrinogen component again after the thrombin component, inject thrombin component again after perhaps injecting fibrinogen component.Similarly, fibrinogen component and thrombin component can be injected intervertebral disc off and on respectively.
[0022] it is to be further understood that one or more site (for example) of injection at the needle point place of spinal needle, can be in fibrous ring or in vertebral pulp.If injection occurs in the vertebral pulp, the component that is injected into can be between vertebral pulp and fibrous ring the speckle of formation at the interface, perhaps, more general situation is, described component flows in damaged (for example crack) of fibrous ring, and " overflow " arrives space between dish probably.In practice, owing to injecting described component to intervertebral disc and excessively exerting pressure of intervertebral disc being avoided.
[0023] injection volume of anesthetis, Fibrinogen and activating compounds is for can seal the damaged amount of given intervertebral disc effectively, and this is tangible for those skilled in the art.The amount of activating compounds such as thrombin can change to some extent, to shorten or to prolong the fibrinous time that is completed into.In general, per unit fibrinogenic level of thrombin is high more, and fibrinous formation is fast more.If want to form more slowly fibrin, then the per unit Fibrinogen uses more a spot of thrombin.Use calcium ion (for example from calcium chloride) in a kind of or two kinds of component solutions, with the fibrinous intensity that influence so forms, along with the amount increase of calcium ion, the intensity of fibrin clot increases.Generally speaking, for the aqueous solution composition of fibrinogen, it is believed that this compositions of the extremely about 5mL of about 3mL is enough to as effective fibrin sealant.But, depending on the purposes of said composition, dosage can be at about 0.05mL to the scope of about 40mL.
[0024] fibrin sealant has imitated the final stage of natural clotting mechanism.Normally, such sealer needs fibrinogen component and activating enzymes mixing of thrombin for example.Thrombin is a kind of enzyme that is present in the blood plasma, and it causes blood coagulation by Fibrinogen is converted into fibrin.In common practice, the component of fibrin sealant was reconstructed respectively by lyophilised state before using.But it also is acceptable using the sample by freezing state or the preparation of new system state.In order to increase the biocompatibility of sealer and host tissue, but each component endogenous ground supply is from host body fluids.The component that merges reconstruct produces viscosity solution, and it becomes the elasticity grumeleuse rapidly.The method of the fibrin sealant that preparation is conventional by J.Rousou etc. at Journal of Thoracic and Cardiovascular Surgery, vol.97, no.2, pp194-203 describes in 1989 2 months.Cryoprecipitate from source blood plasma is washed, is dissolved in the buffer solution, filters and lyophilization.By reconstruct, described solution contains for example aprotinin of 3000 KIU/ milliliters (a kind of multivalence protease inhibitor, prevent the fibrin that forms from degrading too early) to freeze dried Fibrinogen in inhibitors of fibrinolysis solution.This solution is stirred, and is heated to about 37 ℃ temperature.Each solution (thrombin and fibrinogen solution) draws and is placed on the Y type adapter with dual barrel syringe, and syringe needle is connected to this Y type adapter so that carry the solution that merges.(referring to, for example, Duploject device, from immunoAG, the Austria Vienna).Therefore, the mixing of composition only appears in the course of conveying, and this helps grumeleuse and only forms in the site of administration of expectation.Composition should enough promptly be injected, to avoid passage in pin and/or the Y type adapter owing to fibrinous formation is obstructed.
[0025] in one embodiment, the small part that is mixed to of fibrin sealant components is to occur in Y type adapter and be installed in the pin on the Y type adapter, the grumeleuse that takes place in intervertebral disc with equilibrium.This preparation method helps fibrin clot in transport process or promptly be engraved in the desired site formation of intervertebral disc after transmitting.Calcium chloride can be contained in the fibrin sealant to be injected, with the fibrinous composition of modifying formation like this and the clot strength of acquisition.
[0026] in one embodiment, by reconstruct, approximately the thrombin component of 45-55 mg/ml is reconstructed by lyophilised state according to method of the present invention and composition the lyophilizing Fibrinogen of about 75-105 mg/ml independently according to conventional method.Freeze dried Fibrinogen and freeze dried thrombin can obtain from the manufacturer such as Baxter with the form of test kit, and trade name is such as TISEEL .These two kinds of fibrin sealant components for example can be prepared as the approximately sample of 2ml respectively, thereby produce total sealer (thrombin of the fibrinogen plus reconstituted of reconstruct adds anesthetis) of about 4ml.Perhaps, approximately the sealer of 5ml is used altogether, for example, wherein, each 2ml sample of the Fibrinogen of reconstruct and the thrombin of reconstruct is used, and also uses the anesthetis of 1ml, thereby obtains total sealer (thrombin+anesthetis of the fibrinogen plus reconstituted of reconstruct) of about 5ml.
[0027] though several method and composition all can be used for preparing the lyophilized thrombin of using in the fibrin sealant of invention, a kind of method provides the lyophilized thrombin of about 45-55 mg/ml, and it is mixed with reconstituted solutions.The reconstituted solutions that is used for reconstruct thrombin or Fibrinogen or two kinds of components may further include about 0.1～100 milligram other components as herein described (for example local anesthetic or other additives) and/or calcium chloride.The concentration of calcium chloride can be that for example 1-100mmol/mL in one embodiment, is 4-40mmol/mL.If be used, calcium chloride concentration should be enough to promote to form the polyreaction of persistent fibrin sealant clot.The reconstituted solutions that does not contain antiseptic may be supposed to, but is not necessary.
[0028] contrast agent can be used in the injection of fibrin sealant together.Can be before injected injection of contrast medium.Perhaps, contrast agent is comprised in the fibrinogen component or thrombin component that is injected into intervertebral disc.Contrast agent and application thereof are well-known for those skilled in the art.
[0029] Fibrinogen of alternative consumption and concentration and thrombin can be used to form in vivo the fibrin sealant clot of expectation.For example, as mentioned above, can change the amount/concentration of Fibrinogen and/or thrombin, with the Fibrinogen of change merging and viscosity and " hardening time " of thrombin component.Equally, change Fibrinogen, can change the density of the component of merging, this for control through long pipeline for example conduit to enter intravital flowing may be important.Change thrombin, can change the polymerization time of component, this time that forms for the control grumeleuse is to guarantee that described component is in vivo in appropriate site with the time works rather than to work prematurely may be important.
[0030] when obtain be lyophilized form the time, thrombin and Fibrinogen need reconstruct so that use.The thrombin reconstituted solutions (for example) that randomly contains anesthetis and/or one or more additives based on brinish solution, can with in a bottle, prepare before freeze dried thrombin mixes.This component of fibrin sealant can be provided user with reconstituted state then, perhaps, is provided for user with two bottles that do not merge, and contains the reconstituted solutions of freeze dried thrombin and premix in described two bottles respectively.Whenever content in these two bottles can be injected into before the patient in fibrin sealant (perhaps its component), is included in when it injects the patient and mixes.The reconstruct of fibrinogen solution can be finished according to conventional method.For example, fibrinogen component can reconstruct in the aprotinin saline solution, and described solution randomly contains other components, such as, local anesthetic for example.If desired, thrombin or Fibrinogen or both can come reconstruct with the saline solution that contains one or more additives.Make the temperature of all solution reach about 37 ℃.Preferably, use the dual barrel syringe injecting program, thrombin and fibrinogen solution are merged, as described herein, thus form the single sealant compositions that is injected into the patient.The invention provides the instrument that is used to transmit described sealer, it is sent to the precise region at back with described sealer, seals all ring crack cracks, and makes fibrin be in suitable position by the elasticity grumeleuse.In addition, the biodegradable character of the fibrin clot of formation farthest reduces or has eliminated after using effect duration and carried out necessity that invasive surgical removes.Therefore, the advantage of this sealer and methods for using them is, the persistent sealing that can provide a kind of splendid Wicresoft's means to finish the localization in damaged (for example crack) in the fibrous ring, and, if additive is present in the sealer, also can provide the slow release of additive to carry.And when the effect by fibrin sealant brought secular pain relief, anesthetis provided fast, of short duration pain relief.
[0031] uses program well known to those skilled in the art, fibrin sealant can be injected intervertebral disc or other body region.Usually, the trocar (introducer needle) is inserted into the intervertebral disc internal clearance, the position of needle point damaged near in the fibrous ring.The pin of thinner specification (made by for example rustless steel, fibrous ring can puncture) is inserted into the trocar then.Fibrin sealant is injected by the pin of this thinner specification.Perhaps, can use the conduit of making by synthetic polymer.For thinner pin or the conduit made by synthetic polymer, can make this pin or conduit be advanced through the trocar and enter vertebral pulp.Perhaps, this pin or conduit are moved forward until the needle point that arrives the trocar, but not surpass the needle point of this trocar.This can have the advantage of accurate locating injection point, especially because polymeric catheter may bend in vertebral pulp, thus the location that leads to errors.Equally, by the injection site that at first trocar is positioned to expect, thereby fibrin sealant can be injected accelerated procedure apace, and this is useful to the patient.Generally speaking, fibrin sealant of the present invention is injected into intervertebral disc, epidural space, articular process (2-joint) joint (zygaphysical jonit), canalis spinalis and/or dural sac.About the injection of fibrin sealant to intervertebral disc, injection can produce the fibrin matrix of this intervertebral disc of sealing in the intervertebral disc, prevents that the material in the vertebral pulp from leaking into the intervertebral disc exterior domain.For example, fibrin sealant can be transferred by injection in fluoroscopy intervertebral spinal fusion lumber epidural or the intervertebral disc, and for example the U.S. 6,468, described in 527.In order to treat suchlike back injury, fibrin sealant is injected into vertebral pulp, and as shown in fig. 1, with any crack or the hole in the fill fiber ring, sealing intervertebral disc bone soleplate increases the pressure of intervertebral disc, and increases the height of intervertebral space.In general, fibrin sealant is injected near the damaged position of fibrous ring.Usually, fibrin sealant will flow into the crack of fibrous ring, and therefore the agent of some fibre protein blocking may flow out the intervertebral disc internal clearance.Injection also can cover the zone in abutting connection with intervertebral disc, is injected directly into nerve root and peripheral region, and this can protect these zones to avoid the influence of the nucleus material of seepage.Sealing crack and bone soleplate have been prevented the seepage of detrimental substance to the intervertebral disc environment, and have prevented that immune system from causing foreign body reaction at impaired intervertebral disc.Increase intervertebral space, alleviated the pressure on nerve root.That is to say that because this injection, disc height increases, this has increased the gap between the vertebral plate, and this has alleviated the pressure to the nerve root on the vertebral plate then again.For the application,, can promote the reparation of damaged tissues or fibrin sealant progressively to be replaced by the tissue of health with the agent of somatomedin supplementary fibre protein blocking.
[0032] application of Gai Liang fibrin sealant compositions can be better understood by the reference the following examples.These embodiment are representational, should not be interpreted as limiting the scope of the present invention or its claim.(embodiment 3) except as otherwise noted, employed in these embodiments fibrin sealant does not contain corticosteroid, and program is not exist the heating steps of vertebral pulp and fibrous ring and do not carrying out carrying out under the situation of part or all of diskectomy.
Embodiment 1
Fluoroscopy intervertebral spinal fusion epidural injection
[0033] patient lies in on the entablement with attached clinostatism, places and the adjustment fluorescent screen, to locate the intervertebral foramina of affected nerve root.After anesthesia skin and deep tissue, import No. 22 (22ga.) * 3.5 of bending " pin.Under direct X line fluoroscopic observation, this pin is moved forward to before position in the epidural space.The location of this pin is by side position X-ray view with by verifying via this pin injection of contrast medium medium.Such location may need or may not need further adjustment.If be adjusted, then the position of this pin is verified once more.This pin advances and enters correct zone, may with the corresponding to mode stimulation pain of original slight illness.Therefore, the arrangement of pin also can be verified by patient's pain.Epidural space is anaesthetized with injectable anesthetics.Then, the fibrin sealant of fibrinogen and thrombin (before condensing) is imported into via this pin by successive gentle pressure, and the capacity in this dual syringe system is exhausted fully.Described thrombin or Fibrinogen or both are with the solution reconstruct that contains at least a additive.Then, the fibrin sealant bag is by nerve root and fibrous ring, and pin is withdrawn.After this program, observe the patient, the monitoring vital sign carried out about 20-30 minute.
[0034] for this program, the fibrin sealant of sufficient volume is injected, and cuts apart (hydro-dissect) by the zone around the nerve root of targeting with stream power effectively.It is believed that because the no blood vessel attribute of epidural space absorption/degradative phase is longer than viewed absorption/degradative phase in the open applications in the zone that is exposed to room air when having more vascularity and using usually.
[0035] the fibrin sealant ability that can seal the ring crack crack relevant with intervertebral disk hernia provides the treatment benefit for the patient.Known chemical radiculitis or nerve root inflammation are quite painful in some cases.It is believed that in above-described mode and use fibrin sealant, not only coated nerve root, and sealed the ring crack crack around outstanding intervertebral disc.(referring to Fig. 1).Because the stream power of affected nerve root peripheral region is cut apart, this sealer has also been sealed the ring crack crack from the outside of fibrous ring.
Embodiment 2
Injection in the intervertebral disc under the fluoroscopy-guided
[0036] after sterile preparation, the trocar is delivered to the superior articular process in the loxosis projection.The bending spinal needle is delivered to intervertebral disc through the trocar.Anteroposterior position and the X-ray projection of side position are used to confirm correct pin position.If the pin position need be adjusted, then confirm its arrangement by X line perspective once more.Contrast agent is injected to confirm the position of pin.In suffering from the patient of Chemical radiculitis in lumbar spine, can observe contrast agent and by the ring crack crack seepage take place and/or coil interior pathology and can be identified.In case this pin is placed the dish internal clearance rightly, injects fibrin sealant (or its component).Thrombin or Fibrinogen or both are with the solution reconstruct that contains at least a additive.When fibrin sealant is sealed the ring crack crack, observe the contrast agent application of force of this fibrin sealant to the dish internal clearance.Perhaps, contrast agent and sealer together are injected into.Perhaps, do not use contrast agent.This method has been sealed the damaged/crack of fibrous ring, and has stoped chemical leakage and helped the interior recovery of intervertebral disc.
Embodiment 3
Injected and the comparison of injecting the fibrin sealant that contains corticosteroid
[0037] 20 patient is divided into two groups, 10 every group.All patients have the pain that produces because of the disc degeneration that damaged (crack) in the fibrous ring causes.The conventional conservative treatment of all having experienced at least 6 months before all patients does not but take effect really.Use the program among the embodiment 2, injection is to contain the fibrin sealant of Fibrinogen and thrombin in first group of patient's intervertebral disc.Use the program among the embodiment 2, injection is to contain the fibrin sealant of Fibrinogen, thrombin and betamethasone (a kind of corticosteroid) in second group of patient's intervertebral disc.This corticosteroid is in thrombin component.Before operation,, every patient's backache and skelalgia are graded by the 0-10 level with preset time interval, operation back.Result's (VAS mark) is shown among Fig. 3 and Fig. 4.Just as can be seen, with respect to the patient who injects with the fibrin sealant that contains betamethasone, the patient experience of injecting with independent fibrin sealant (not containing betamethasone) excellent pain relief.Once imputedly be, the patient who accepts to comprise the injection of betamethasone has excellent effect, and reason is that betamethasone has the effect that reduces inflammation.Yet observed situation is opposite.In fact, only injected with the patient experience of fibrin sealant the pain relief of obvious improvement, this be not only after operation 1 week, and 12 weeks after operation especially.These results are amazing and unexpected.
Embodiment 4
The fibrin sealant that comprises local anesthetic
[0038] program among the use embodiment 2, injection is to contain the fibrin sealant of Fibrinogen, thrombin and local anesthetic (bupivacaine hydrochloride) in patient's intervertebral disc.Local anesthetic solution (approximately 1mL) is mixed into and is used for the fibrinogenic calcium chloride solution of reconstruct.The total amount of injected fibrin sealant thereby be 5mL.Find that surprisingly with respect to the fibrin sealant of fibrin sealant that contains corticosteroid or embodiment 3, the fibrin sealant that comprises local anesthetic all provides more excellent effect.
Embodiment 5
The fibrin sealant that has local anesthetic
[0039] patient treats with the fibrin sealant that contains local anesthetic.This local anesthetic is used to the reconstruct thrombin.The patient is suffering the pain that produces owing to disc degeneration that damaged (crack) in the fibrous ring causes.Use the method among the embodiment 2, the patient is injected to contain the fibrin sealant of Fibrinogen, thrombin and local anesthetic (75% bupivacaine of 3cc) in the intervertebral disc.Local anesthetic is used to the reconstruct thrombin.Fibrinogen, thrombin and local anesthetic 5cc are altogether injected.The operation before and the operation after predetermined time interval, patient's backache and skelalgia are graded by the 0-10 level.For backache, the result is as follows: before the treatment, and 4; Treatment one week of back, 4; Treatment three weeks of back, 1; Treatment six weeks of back, 1.Before treatment and after the treatment, skelalgia all is 0.Because pain significantly alleviating after six weeks, these results are astonishing and unexpected.
[0040] suspect, by using fibrin sealant to be similar to the mode described in the foregoing description, the present invention can be with solving various condition of illness.Specific device, material and embodiment have been quoted in discussion of the present invention, these elaborations the limited application of claimed invention.The present invention is not limited to these particular cases, but is applicable to all equivalents.Although the present invention is described with reference to specific device, material and embodiment, should be appreciated that the present invention is not limited to these particular cases that is disclosed, on the contrary, can extend to all equivalents within the scope of the claims.
Claims (80)
1. method for the treatment of intervertebral disc, described intervertebral disc is by at least one the damaged seepage vertebral pulp in the fibrous ring, described method comprises: inject fibrin sealant to reduce described at least one damaged segmental defect at least to described intervertebral disc, the described fibrin sealant that wherein is injected into described intervertebral disc comprises anesthetis, Fibrinogen and activating compounds, wherein be formed up to the described fibrin of small part after injection, condition is that the described fibrin sealant that is injected into described intervertebral disc lacks corticosteroid.
2. the method for claim 1, condition is that described vertebral pulp and described fibrous ring all are not heated.
3. the process of claim 1 wherein that described fibrin sealant is made up of Fibrinogen, activating compounds and anesthetis, optional at least a additive and optional calcium chloride basically.
4. the process of claim 1 wherein that described fibrin sealant formed, and randomly contained calcium chloride by Fibrinogen, activating compounds and anesthetis, optional at least a additive.
5. the process of claim 1 wherein that calcium chloride and described Fibrinogen and described activating compounds are injected together.
6. the process of claim 1 wherein that described activating compounds is a thrombin.
7. the process of claim 1 wherein that described method is made of injecting step.
8. the process of claim 1 wherein that described anesthetis is lignocaine, sarapin or bupivacaine.
9. the process of claim 1 wherein that at least a additive is also injected.
10. the process of claim 1 wherein and be removed by operation without any described vertebral pulp partly.
11. the process of claim 1 wherein described at least one damaged be tearing or the crack in the described fibrous ring.
12. the process of claim 1 wherein that the normal fluid static pressure in the described intervertebral disc is resumed.
13. the process of claim 1 wherein that normal disc height is resumed.
14. the process of claim 1 wherein that described Fibrinogen is from body.
15. the process of claim 1 wherein that described injection is by using dual barrel syringe to implement.
16. the process of claim 1 wherein that described activating compounds is a thrombin, and wherein the mixture of anesthetis, Fibrinogen and thrombin is injected.
17. the process of claim 1 wherein that described activating compounds is a thrombin, and wherein said Fibrinogen and thrombin injected successively, and in described intervertebral disc, mixed at least in part.
18. the process of claim 1 wherein described anesthetis before described Fibrinogen and thrombin, simultaneously or sequentially injected afterwards, and in described intervertebral disc, mix at least in part.
19. the process of claim 1 wherein that described intervertebral disc injects in a plurality of sites with described fibrin sealant.
20. the process of claim 1 wherein that described injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.
21. the process of claim 1 wherein that described intervertebral disc is a lumbar intervertebral disc.
22. the process of claim 1 wherein that described intervertebral disc is a cervical intervertebral disk.
23. the process of claim 1 wherein that described intervertebral disc is a thoracic disc.
24. the process of claim 1 wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.
25. method for the treatment of the people back, comprise that fibrin sealant is injected intervertebral disc is damaged to seal at least one of fibrous ring, wherein said fibrin sealant comprises anesthetis, Fibrinogen and thrombin, wherein said Fibrinogen and thrombin are formed up to the described fibrin of small part after injection, and wherein said fibrin sealant does not comprise corticosteroid.
26. being described vertebral pulp and described fibrous ring, the method for claim 25, condition all be not heated.
27. the method for claim 25, wherein said fibrin sealant are made up of anesthetis, Fibrinogen, activating compounds and optional at least a additive basically.
28. the method for claim 25, wherein said fibrin sealant is made up of anesthetis, Fibrinogen, activating compounds, optional at least a additive and calcium chloride.
29. the method for claim 25, wherein calcium chloride and described anesthetis, Fibrinogen and described thrombin are injected together.
30. the method for claim 25, wherein said method is made of injecting step.
31. the method for claim 25, wherein said activating compounds is a thrombin.
32. the method for claim 25, wherein at least a additive is also injected, and wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Collagen hydrolysate; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.
33. the method for claim 25, wherein said anesthetis is local anesthetic, and wherein said local anesthetic is lignocaine, sarapin or bupivacaine.
34. the method for claim 25, wherein the described vertebral pulp without any part is removed by operation.
35. the method for claim 25, wherein said at least one damaged be tearing or the crack in the described fibrous ring.
36. the method for claim 25, the normal fluid static pressure in the wherein said intervertebral disc is resumed.
37. the method for claim 25, wherein normal disc height is resumed.
38. the method for claim 25, wherein said Fibrinogen is from body.
39. the method for claim 25, wherein said injection are by using dual barrel syringe to implement.
40. the method for claim 25, wherein said activating compounds is a thrombin, and wherein the mixture of Fibrinogen and thrombin is injected.
41. the method for claim 25, wherein said activating compounds is a thrombin, and wherein said Fibrinogen and thrombin successively injected, and mixes in described intervertebral disc at least in part.
42. the method for claim 25, wherein said intervertebral disc is injected with a plurality of sites of described fibrin sealant in described intervertebral disc.
43. the method for claim 25, wherein said injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.
44. the method for claim 25, wherein said intervertebral disc is a lumbar intervertebral disc.
45. the method for claim 25, wherein said intervertebral disc is a cervical intervertebral disk.
46. the method for claim 25, wherein said intervertebral disc is a thoracic disc.
47. the method for claim 25, wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.
48. a method for the treatment of the people back, it is damaged with at least one of treatment fibrous ring to be included in mixture that anesthetis, Fibrinogen and thrombin are provided in the human disc, and wherein said mixture does not comprise corticosteroid.
49. being described vertebral pulp and described fibrous ring, the method for claim 48, condition all be not heated.
50. the method for claim 48, wherein said fibrin sealant are made up of anesthetis, Fibrinogen, thrombin and optional at least a additive basically.
51. the method for claim 48, wherein said fibrin sealant is made up of anesthetis, Fibrinogen, thrombin, optional at least a additive and calcium chloride.
52. the method for claim 48, wherein calcium chloride and described Fibrinogen and described thrombin are provided together.
53. the method for claim 48, wherein said method is made of the described step that provides.
54. the method for claim 48, wherein at least a additive also is provided, and wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Collagen hydrolysate; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.
55. the method for claim 48, wherein said anesthetis is local anesthetic, and wherein this local anesthetic is lignocaine, sarapin or bupivacaine.
56. the method for claim 48, wherein the described vertebral pulp without any part is removed by operation.
57. the method for claim 48, wherein said at least one damaged be tearing or the crack in the described fibrous ring.
58. the method for claim 48, the normal fluid static pressure in the wherein said intervertebral disc is resumed.
59. the method for claim 48, wherein normal disc height is resumed.
60. the method for claim 48, wherein said Fibrinogen is from body.
61. the method for claim 48, wherein said providing is by using dual barrel syringe to implement.
62. the method for claim 48, wherein Fibrinogen, thrombin and described narcotic mixture are provided.
63. the method for claim 48, wherein said Fibrinogen and thrombin are successively provided, and mix in described intervertebral disc at least in part.
64. the method for claim 48, the wherein said intervertebral disc a plurality of sites in this intervertebral disc are provided to described fibrin sealant.
65. the method for claim 48, wherein said injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.
66. the method for claim 48, wherein said intervertebral disc is a lumbar intervertebral disc.
67. the method for claim 48, wherein said intervertebral disc is a cervical intervertebral disk.
68. the method for claim 48, wherein said intervertebral disc is a thoracic disc.
69. the method for claim 48, wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.
70. test kit comprises: anesthetis, Fibrinogen, thrombin, optional at least a additive, spinal needle, wherein said test kit does not comprise corticosteroid, and described test kit does not comprise the device that heat energy is provided to intervertebral disc.
71. the test kit of claim 70, wherein said anesthetis is local anesthetic, and wherein said local anesthetic is lignocaine, sarapin or bupivacaine.
72. the test kit of claim 70 also comprises calcium chloride.
73. the test kit of claim 70, wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Collagen hydrolysate; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1) LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.
74. the test kit of claim 70, wherein said Fibrinogen and thrombin are lyophilised states.
75. the test kit of claim 70 also comprises the trocar.
76. the test kit of claim 70, wherein the size of polymeric catheter makes it can not extend beyond the needle point of the trocar during use.
77. produce the method for test kit, comprise: fibrinogen component is provided, thrombin component, the anesthetis component, and spinal needle or polymeric catheter or spinal needle and polymeric catheter, wherein said test kit does not comprise corticosteroid, and described test kit does not comprise the device that heat energy is provided to intervertebral disc.
78. the method for claim 77, the size of wherein said polymeric catheter make it can not extend beyond the needle point of the described trocar during use.
79. the method for claim 77, the size of wherein said spinal needle make it can not extend beyond the needle point of the described trocar during use.
80. second solution that contains fibrinogenic first solution and contain thrombin is used for the treatment of application in the pharmaceutical composition of the mammal intervertebral disc of seepage vertebral pulp because at least one in the fibrous ring is damaged in preparation, wherein said first solution and second solution all do not contain corticosteroid, and wherein anesthetis is present among described first solution, described second solution or both.
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| Application Number | Priority Date | Filing Date | Title |
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| US62360004P | 2004-10-29 | 2004-10-29 | |
| US60/623,600 | 2004-10-29 | ||
| US11/205,775 | 2005-08-17 |
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| CN 200580036812 Pending CN101052426A (en) | 2004-10-29 | 2005-10-31 | Injection of fibrin sealant including an anesthetic in spinal applications |
| CN 200580036813 Pending CN101048190A (en) | 2004-10-29 | 2005-10-31 | Injection of fibrin sealant using reconstituted components in spinal applications |
| CN 200580036811 Pending CN101048189A (en) | 2004-10-29 | 2005-10-31 | Injection of fibrin sealant in the absence of corticosteroids in spinal applications |
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| CN108514643A (en) * | 2018-04-18 | 2018-09-11 | 曾奕明 | A kind of small pulmonary nodules carry out operation consent color and tactile markings method |
| CN113546697A (en) * | 2020-04-23 | 2021-10-26 | 国家纳米科学中心 | Microfluidic device and preparation method and application thereof |
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| CN103881972B (en) * | 2013-08-28 | 2015-08-26 | 中国人民解放军***福州总医院 | A kind of method being applicable to mesenchymal stem cell serum-free and cultivating |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108514643A (en) * | 2018-04-18 | 2018-09-11 | 曾奕明 | A kind of small pulmonary nodules carry out operation consent color and tactile markings method |
| CN113546697A (en) * | 2020-04-23 | 2021-10-26 | 国家纳米科学中心 | Microfluidic device and preparation method and application thereof |
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